PROJECT SUMMARY/ABSTRACT Defects in endo-lysosomal system are common mechanisms in neurodegenerative diseases. Elucidating key functions of endosomal proteins will provide crucial insight into the neurodegenerative pathologies such as Alzheimer?s disease (AD) and AD-related dementias (AD/ADRD). The goal of this research is to define cellular mechanism mediated by the endosomal Na+/H+ exchanger 6 (NHE6) protein in aging process and neurodegenerative diseases in our novel NHE6-null rat model. Loss-of-function mutations in NHE6 cause Christianson syndrome (CS) in males, involving neurodevelopmental and neurodegenerative pathologies. NHE6 mutations are being actively studied in AD/ADRD pathologies, including as they may relate to pathological tau deposition in aging. However, a hindrance in this field is that mouse models do not recapitulate key neurodegenerative pathologies, including tau pathology. To overcome this, we generated a new NHE6-null rat model. Rats are genetically and physiologically closer to human than mice. Importantly, the rat model improves on current mouse models by manifesting endogenous defects of tau processing. Our specific aims are: 1) Demonstrate neurodegeneration and tau pathology in the novel aging CS rat model; 2) Determine the mechanisms whereby loss of NHE6 function disrupts late endosome maturation, resulting in aberrant retrograde axonal transport. We take multidisciplinary approaches such as biochemical methods and super-resolution imaging techniques. The proposed work will provide better understanding of mechanisms that may become a therapeutic target for AD/ADRD.